The program is a multidisciplinary, collaborative effort which is a continuation of ongoing research involving investigators at the Massachusetts Institute of Technology and the Massachusetts General Hospital. The hypothesis of this proposal is that optical coherence tomography, a new optical diagnostic imaging technology for in situ imaging of tissue microstructure, can be developed and applied for "optical biopsy," the in situ diagnosis and monitoring of early neoplastic changes. The proposed program will consist of several components with complementary aims. Studies will be performed with existing OCT technology operating at image resolutions of 15-20 microns to examine neoplastic changes in tissue from various organ systems and establish correspondence with histopathology. Though some neoplastic changes such as glandular hypertropy are likely to occur at this resolution, some malignancies, such as cervical carcinoma, will likely require highter resolution to allow nuclear analysis. OCT technology will be developed in order to extend the limit of imaging resolution to the 3-4 micron scale to permit this cellular and subcellular level imaging. High resolution imaging studies and correspondence with histopathology will then be performed on selected tissue pathologies in order to evaluate the ability to visualize microstructure changes critical in identifying neoplastic transformation. We expect that imaging at 3-4 micron resolution should be an enabling step toward a wide range of diagnostic applications. In order to develop the foundation for in vivo studies, we will develop a forward scanning rigid endoscope and a forward scanning flexible catheter/endoscope. Together with a transverse scanning OCT catheter that we have already developed, we will perform in vivo imaging studies of normal tissue of the GI, urinary, reproductive, and respiratory tracts in a normal animal model. These studies will identify issues which must be addressed in vivo imaging studies and possible differences between in vitro and in vivo imaging. Finally we will perform in vivo imaging studies using the hamster cheek pouch carcinoma model to evaluate the ability of OCT to image premalignant and malignant changes in vivo. Taken together, these studies hold the promise of developing a new imaging diagnostic which could be a powerful tool in the diagnosis and prevention of malignancy.